A two years longitudinal study of a transgenic Huntington disease monkey

Abstract

Background: A two-year longitudinal study composed of morphometric MRI measures and cognitive behavioral evaluation was performed on a transgenic Huntington's disease (HD) monkey. rHD1, a transgenic HD monkey expressing exon 1 of the human gene encoding huntingtin (HTT) with 29 CAG repeats regulated by a human polyubiquitin C promoter was used together with four age-matched wild-type control monkeys. This is the first study on a primate model of human HD based on longitudinal clinical measurements.

Results: Changes in striatal and hippocampal volumes in rHD1 were observed with progressive impairment in motor functions and cognitive decline, including deficits in learning stimulus-reward associations, recognition memory and spatial memory. The results demonstrate a progressive cognitive decline and morphometric changes in the striatum and hippocampus in a transgenic HD monkey.

Conclusions: This is the first study on a primate model of human HD based on longitudinal clinical measurements. While this study is based a single HD monkey, an ongoing longitudinal study with additional HD monkeys will be important for the confirmation of our findings. A nonhuman primate model of HD could complement other animal models of HD to better understand the pathogenesis of HD and future development of diagnostics and therapeutics through longitudinal assessment.

Figure 1

Expression pattern of mutant HTT and brain volumetric measurements in a transgenic HD monkey and control monkeys. (a) Quantitative measurement of mutant HTT transcript in controls and rHD1 peripheral blood at four time-points by quantitative PCR, (b) Western blot analysis of one of the control monkeys and rHD1 at various time points. Arrow indicates the expression of soluble form mutant HTT protein that was not observed in control monkey samples. (c) Longitudinal measurement of body weight. (d) Longitudinal measurement of head circumference. Longitudinal morphometric measurements of (e) hippocampus and (f) striatum at four time-points by MRI normalized with total brain volume.

Figure 2

Infant neurobehavioral assessment scale results. Scores are rated for (a) orienting responses (visual orienting and following, attention span, auditory orienting), (b) neuromotor abilities (muscle tonus prone and supine, pull-to-sit, coordination and response speed), (c) motor activities (locomotion and coordination), and (d) temperament (vocal reactions, fearfulness, struggle, irritability, consolability during testing) for four controls (white bar) and rHD1. Controls are represented by mean value with SEM error bar.

Figure 3

For measures of stimulus-reward associations and flexible behavioral inhibition, scores are the number of errors committed until reaching the criterion for (a) pattern discrimination at eight months, (b) concurrent discrimination at nine months and (c) object discrimination reversal at 12 months for the four controls and rHD1. For measures of cognitive inhibition and impulsivity, scores are number of total reaches, barrier reaches and perseverative reaches during the (d) “Easy” trials (box opened left or right and reward positioned at the box entrance), (e) “Moderate” trials (box opened right or left and reward positioned mid-way inside the box), and (f) “Difficult” trials (box opened right or left and reward positioned on the opposite side of the box) for the four controls (Mean ± SEM, open bars) and rHD1 (solid bars).

Figure 4

The impairment in hippocampal-dependent memory functions in rHD1. Scores are percent correct when looking at novel objects at four different delays (a) 10s, 30s, 60s, 120s in the VPC (Visual Paired Comparison) task at four months and (b) percent correct at delays of 30s, 60s, 120s, and 600s in the DNMS (Delayed Nonmatching-to-Sample) task at 18 months for the four controls (open circle and dashed line) and rHD1 (close circles and solid line). Controls are represented by mean value with SEM error bar.